Spatial-temporal signals determine the fate of activated CD8⁺ T cells. The balance between TLR-induced proinflammatory and apoptotic signals via STAT1 pathways in activating DCs and subsequent induction of negative feedback loops that initiate anti-inflammatory signals via the STAT3 axis define the narrow window of DC competency for polarizing CD4⁺ Th1 responses and cross-presentation of antigen to CD8⁺ T cells. TCR recognition of pMHC results in rapid down-regulation of CD62L, SIP1, and IL-7R, up-regulation of activation markers, and acquisition of effector function. During the next 3 to 4 days, Th1 CD4⁺ and CD8⁺ T cells proliferate in response to autocrine and paracrine IL-2, produce IFN-γ, and up-regulate CTLA-4. CTLA-4 ligation on DCs leads to indoleamine 2,3-dioxygenase (IDO) up-regulation, Foxo3-mediated inhibition of IL-6 production, and a shift from competency to induction of regulatory T cells, anergy, and cell death. This is the cue for activated CD4⁺ and CD8⁺ T cells to egress from secondary lymphoid organs. Foxo1 and KLF2 transcription factors, regulated by posttranscriptional modifications, coordinate renewed expression of the IL-7R, CD62L, CCR7, and S1P1, and down-regulate inflammatory chemokine receptors, respectively, on cells destined to become T central memory (Tcm) cells. In contrast, both IL-2 and IL-4 suppress Kruppel-like factor 2 (KLF2) expression and signals transmitted through IL-4R/ STAT6 up-regulate Eomes which induces expression of CXCR3 on CD8⁺ T cells. Survival after cytokine deprivation is dependent on costimulatory and other survival signals received before egress from lymphoid tissue. Limiting growth factors cause activated T cells to shutdown growth and proliferative programs sustained through TCR/CD28, and IL-2 and the P13K/AKT/mTOR pathway and to up-regulate autophagy pathways during transit into nonactivated lymphoid tissue and tissue niches. Here, T central memory (Tcm) and T effector memory (Tem) cell populations become dependent upon cytokine and tissue-specific interactions for maintenance and homeostasis. CD8⁺ T cells that receive CD4-proficient help in T cell–rich zones of draining lymph nodes may be more destined for long-term survival. The balance between costimulatory signals that up-regulate antiapoptotic factors, and negative costimulatory molecules up-regulated during the effector phase such as CTLA-4, BTLA-4, and PD1 (during chronic stimulation) that block effector function ultimately determine the population of cells that survive and transit into the memory pool. Expression of CD8⁺ effector function is regulated by 2 T box–binding transcription factors, Tbet and eomesodermin (Eomes). Although both Tbet and Eomes are essential inducers of CD8⁺ T-cell IFN-γ, perforin, granzyme B, and cytolytic capability, how these 2 transcription factors are coordinately regulated to control effector function and transition to long-term memory is unclear. During the inductive phase of the immune response, IL-12 and IFN-γ drive the differentiation and expansion of CD4⁺ Th1 and CD8⁺ T effector cells. This is reflected in the levels of T-bet expression and secreted osteopontin. During late-stage effector differentiation, inhibitor of DNA binding 2 (Id2), an antagonist of E protein transcription factors is up-regulated by CD8⁺ T cells and maintained in effector memory cells.⁴⁷  E proteins are basic helix-loop-helix family of transcriptional activators and repressors, which bind specifically to DNA sequences containing the E-box consensus sequence. E protein homodimers regulate a complex array of genes during T-cell differentiation including expression of CD127 and CD27. Members of helix-loop-helix (HLH) protein family of Id (inhibitor of differentiation) dimerize with bHLH transcription factors and function as negative regulators of differentiation and promote progression of cells into S phase. E-Id2 heterodimer formation leads to diminished E-box–mediated gene expression such as Ctla4 and Bcl2l11 (BimEL) associated with reduced survival of T effector cells and relieves E protein repression of Serpinb9 coding for the serine protease inhibitor (Spi-6) thought to protect cytolytic effector cells from programmed cell death. Thus, Id-2 regulates the size of the Tem (CD62L^low, CD122^lowCD127^lowCD27^high) subset in addition to regulating the survival of effector CD8⁺ T cells. Understanding transcriptional programs that control proliferation, acquisition of effector function, and survival of CD4⁺ and CD8⁺ T cells during the immune response will be key to developing new vaccine strategies.